Featured Publications
Mechanism of Insulin Action
White M. Mechanism of Insulin Action. 2024, 111-127. DOI: 10.1002/9781119697473.ch9.Peer-Reviewed Original ResearchReceptor tyrosine kinasesTyrosine kinaseGrowth factor signalingSecrete sufficient insulinDysregulated insulin signalingPancreatic beta cellsMuscle insulin resistanceEnvironmental signalsSignal transductionInsulin signalingMuscle-specific deletionSystemic insulin actionSystemic insulin resistanceAdequate insulin responseFactor signalingInsulin-like growth factor signalingPlasma membraneInsulin resistanceInsulin receptorLigand bindingBeta cellsMetabolic stressChronic insulin resistanceGlucose transportTransphosphorylationBRD7 improves glucose homeostasis independent of IRS proteins.
Kim Y, Lee J, Han Y, Tao R, White M, Liu R, Park S. BRD7 improves glucose homeostasis independent of IRS proteins. Journal Of Endocrinology 2023, 258 PMID: 37578842, PMCID: PMC10430774, DOI: 10.1530/joe-23-0119.Peer-Reviewed Original ResearchConceptsGlucose homeostasisKnockout miceAlternative insulinObese miceGlucose homeostasis independentGlucose metabolism parametersContext of obesityBlood glucose levelsMetabolism parametersGlucose levelsGlucose metabolismInsulinMiceIRS proteinsInsulin receptorProtein 7ObesityHomeostasisUpregulationBRD7InvolvementPathwayNovel insightsEuglycemiaFindings1632-P: Effects of MTOR Signaling in Muscle-Specific Irs1/2 Knockout Mice
STOEHR O, COPPS K, TAO R, WHITE M. 1632-P: Effects of MTOR Signaling in Muscle-Specific Irs1/2 Knockout Mice. Diabetes 2023, 72 DOI: 10.2337/db23-1632-p.Peer-Reviewed Original ResearchMTKO miceGlucose uptakeMTOR pathwayMdKO miceReduced ejection fractionCardiac fatty acid uptakeHigh-fat dietInsulin-resistant heartMuscle glucose uptakeDays of lifeWhite adipose tissueCardiac glucose uptakeFatty acid uptakeEffects of mTORInsulin-stimulated conditionsEjection fractionFat dietFat massMuscle atrophyIRS2 expressionCardiac hypertrophyEarly deathCardiac energyKnockout miceAdipose tissueHepatic follistatin increases basal metabolic rate and attenuates diet-induced obesity during hepatic insulin resistance
Tao R, Stöhr O, Wang C, Qiu W, Copps K, White M. Hepatic follistatin increases basal metabolic rate and attenuates diet-induced obesity during hepatic insulin resistance. Molecular Metabolism 2023, 71: 101703. PMID: 36906067, PMCID: PMC10033741, DOI: 10.1016/j.molmet.2023.101703.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceInsulin resistanceAdipose massBasal metabolic rateHepatic disruptionDiet-induced obesityFat mass accumulationTotal lean massHigh-fat dietBody weight changesHFD consumptionFat massLean massFOXO1-dependent mannerHepatic overexpressionHepatic insulinObesityMetabolic rateThe role of hepatokines in NAFLD
Stefan N, Schick F, Birkenfeld A, Häring H, White M. The role of hepatokines in NAFLD. Cell Metabolism 2023, 35: 236-252. PMID: 36754018, PMCID: PMC10157895, DOI: 10.1016/j.cmet.2023.01.006.Peer-Reviewed Original ResearchConceptsNon-alcoholic fatty liver diseaseNon-communicable diseasesInsulin resistanceVisceral obesityMajor non-communicable diseasesRole of hepatokinesFatty liver diseaseRole of fetuinVisceral adiposityFatty liverLiver diseaseCardiometabolic diseasesPathophysiological mechanismsOrgan crosstalkHepatokinesMain pathomechanismClinical practiceImportant causeDiseasePrecision medicineAdipokinesObesityMetabolismAdiposityPathomechanismLower Hepatic Fat Is Associated With Improved Insulin Secretion in a High-Risk Prediabetes Subphenotype During Lifestyle Intervention
Wagner R, Heni M, Kantartzis K, Sandforth A, Machann J, Schick F, Peter A, Fritsche L, Szendrödi J, Pfeiffer A, Schürmann A, Blüher M, Hauner H, Seissler J, Bornstein S, Roden M, Stefan N, Birkenfeld A, White M, Häring H, Fritsche A. Lower Hepatic Fat Is Associated With Improved Insulin Secretion in a High-Risk Prediabetes Subphenotype During Lifestyle Intervention. Diabetes 2022, 72: 362-366. PMID: 36525512, PMCID: PMC9935494, DOI: 10.2337/db22-0441.Peer-Reviewed Original ResearchConceptsInsulin secretionLifestyle interventionLiver fatOral glucose tolerance testHigh liver fatLifestyle intervention studyGlucose tolerance testHigh-risk clustersHepatic fatTolerance testInsulin sensitivitySpecific subphenotypesIntervention studiesSecretionTime pointsInterventionPrediabetesGlycemic traitsFatSubphenotypesGlycemiaCluster 3Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex
Xie L, Yuan Y, Xu S, Lu S, Gu J, Wang Y, Wang Y, Zhang X, Chen S, Li J, Lu J, Sun H, Hu R, Piao H, Wang W, Wang C, Wang J, Li N, White M, Han L, Jia W, Miao J, Liu J. Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex. Cell Reports 2022, 41: 111498. PMID: 36261001, PMCID: PMC10153649, DOI: 10.1016/j.celrep.2022.111498.Peer-Reviewed Original ResearchConceptsNon-alcoholic fatty liver diseaseFatty liver diseaseLipid metabolism diseasesLipid catabolismHepatic lipid catabolismFatty acid oxidationDetectable hepatotoxicityCopper deficiencyNAFLD developmentLiver diseaseMetabolic diseasesMetabolism diseasesNormal levelsDiseaseMitochondrial biogenesisAcid oxidationAMPK activityAMPKAblationDeficiencyCatabolismLKB1HepatotoxicityThe P300 acetyltransferase inhibitor C646 promotes membrane translocation of insulin receptor protein substrate and interaction with the insulin receptor
Peng J, Ramatchandirin B, Wang Y, Pearah A, Namachivayam K, Wolf R, Steele K, MohanKumar K, Yu L, Guo S, White M, Maheshwari A, He L. The P300 acetyltransferase inhibitor C646 promotes membrane translocation of insulin receptor protein substrate and interaction with the insulin receptor. Journal Of Biological Chemistry 2022, 298: 101621. PMID: 35074429, PMCID: PMC8850660, DOI: 10.1016/j.jbc.2022.101621.Peer-Reviewed Original ResearchConceptsAbsence of insulinP300 acetyltransferase activityTyrosine kinase activityAcetyltransferase activityInsulin receptorObese patientsTyrosine phosphorylationRole of acetylationInsulinNormal functionMembrane translocationSubsequent activationC646PatientsLiver hepatocytesProtein substratesInhibitionReceptorsMolecular mechanismsHepatocytesPhosphorylationBeta subunitKinase activityObesityUnique effectsElevated circulating follistatin associates with an increased risk of type 2 diabetes
Wu C, Borné Y, Gao R, López Rodriguez M, Roell W, Wilson J, Regmi A, Luan C, Aly D, Peter A, Machann J, Staiger H, Fritsche A, Birkenfeld A, Tao R, Wagner R, Canouil M, Hong M, Schwenk J, Ahlqvist E, Kaikkonen M, Nilsson P, Shore A, Khan F, Natali A, Melander O, Orho-Melander M, Nilsson J, Häring H, Renström E, Wollheim C, Engström G, Weng J, Pearson E, Franks P, White M, Duffin K, Vaag A, Laakso M, Stefan N, Groop L, De Marinis Y. Elevated circulating follistatin associates with an increased risk of type 2 diabetes. Nature Communications 2021, 12: 6486. PMID: 34759311, PMCID: PMC8580990, DOI: 10.1038/s41467-021-26536-w.Peer-Reviewed Original ResearchConceptsAdipose tissue insulin resistanceTissue insulin resistanceType 2 diabetesFollistatin levelsGlucokinase regulatory protein geneFollistatin secretionHazard ratioInsulin resistanceNon-alcoholic fatty liver diseaseAdjusted hazard ratioFatty liver diseaseRisk of T2DFree fatty acid releaseFatty acid releaseIncident T2DLiver diseaseGenome-wide association studiesHuman adipocytesT2DAcid releaseStandard deviation increaseDiabetesSecretionRiskRegulatory protein geneTAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiological states
Xu S, Liu Y, Hu R, Wang M, Stöhr O, Xiong Y, Chen L, Kang H, Zheng L, Cai S, He L, Wang C, Copps K, White M, Miao J. TAZ inhibits glucocorticoid receptor and coordinates hepatic glucose homeostasis in normal physiological states. ELife 2021, 10: e57462. PMID: 34622775, PMCID: PMC8555985, DOI: 10.7554/elife.57462.Peer-Reviewed Original ResearchConceptsGluconeogenic gene promotersBinding of GRGene promoterGlucocorticoid receptorGlucose homeostasisLigand-binding domainGlucose productionOverexpression of TAZHepatic glucose homeostasisWW domainsBlood glucose concentrationPhysiological fastingGluconeogenic genesGR response elementResponse elementNovel roleTAZNormal physiological stateGR transactivationPhysiological statePromoterMouse liverPericentral hepatocytesPathological statesGlucose concentration
2021
Insulin action at a molecular level – 100 years of progress
White M, Kahn C. Insulin action at a molecular level – 100 years of progress. Molecular Metabolism 2021, 52: 101304. PMID: 34274528, PMCID: PMC8551477, DOI: 10.1016/j.molmet.2021.101304.Peer-Reviewed Original ResearchConceptsAmino acid sequenceType 2 diabetesFunction of insulinAcid sequenceMolecular knowledgeHuman diseasesInsulin-sensitive tissuesPhysiological functionsPhysiological roleInsulin receptorInsulin-resistant statesInsulin 100 yearsInsulin actionBlood glucoseCascadeInsulinDiabetesTissueDiscoveryRegulationTreatmentRemarkable advancesRoleSequenceYearsErratum. Inhibition of TNF-α Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes. Diabetes 2012;61:2134–2145
Wang Z, Cheng Z, Cristofaro V, Li J, Xiao X, Gomez P, Ge R, Gong E, Strle K, Sullivan M, Adam R, White M, Olumi A. Erratum. Inhibition of TNF-α Improves the Bladder Dysfunction That Is Associated With Type 2 Diabetes. Diabetes 2012;61:2134–2145. Diabetes 2021, 70: 1416-1416. PMID: 33980694, PMCID: PMC8275895, DOI: 10.2337/db21-er06c.Peer-Reviewed Original ResearchIrs2 deficiency alters hippocampus-associated behaviors during young adulthood
Tanokashira D, Wang W, Maruyama M, Kuroiwa C, White M, Taguchi A. Irs2 deficiency alters hippocampus-associated behaviors during young adulthood. Biochemical And Biophysical Research Communications 2021, 559: 148-154. PMID: 33940386, PMCID: PMC8361845, DOI: 10.1016/j.bbrc.2021.04.101.Peer-Reviewed Original ResearchConceptsYoung adult male miceAdult male miceMale miceAlzheimer's diseaseType 2 diabetes mellitusInsulin-like growth factor-1Brain energy metabolismGrowth factor-1Young adult malesCore body temperatureDiabetes mellitusInsulin resistanceInsulin/insulin-like growth factor-1Risk factorsBehavioral alterationsCognitive impairmentGenetic backgroundPremature deathHippocampusMiceYoung adulthoodAberrant alterationsFactor 1Abnormal changesBody temperatureFoxO1 suppresses Fgf21 during hepatic insulin resistance to impair peripheral glucose utilization and acute cold tolerance
Stöhr O, Tao R, Miao J, Copps K, White M. FoxO1 suppresses Fgf21 during hepatic insulin resistance to impair peripheral glucose utilization and acute cold tolerance. Cell Reports 2021, 34: 108893. PMID: 33761350, PMCID: PMC8529953, DOI: 10.1016/j.celrep.2021.108893.Peer-Reviewed Original ResearchMeSH KeywordsAdaptation, PhysiologicalAdipocytes, BrownAdipose Tissue, BrownAnimalsBlood GlucoseBody WeightCold TemperatureDiet, High-FatFibroblast Growth FactorsForkhead Box Protein O1Gene Expression RegulationGlucoseHomeostasisInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLipid MetabolismLiverMice, KnockoutOrgan SpecificityOxidation-ReductionThermogenesisConceptsHepatic insulin resistanceInsulin resistanceGlucose utilizationHigher plasma Fgf21 levelsSevere hepatic insulin resistanceFGF21 knockout micePlasma FGF21 levelsPeripheral glucose utilizationInsulin-resistant miceThermogenic gene expressionFGF21 resistancePharmacologic formsFGF21 levelsCold intoleranceFGF21 functionMetabolic healthBAT functionGlucose homeostasisKnockout miceFGF21Adenoviral infectionMiceWeight lossSkeletal muscleAcute cold toleranceInsulin receptor substrate 1, but not IRS2, plays a dominant role in regulating pancreatic alpha cell function in mice
Takatani T, Shirakawa J, Shibue K, Gupta M, Kim H, Lu S, Hu J, White M, Kennedy R, Kulkarni R. Insulin receptor substrate 1, but not IRS2, plays a dominant role in regulating pancreatic alpha cell function in mice. Journal Of Biological Chemistry 2021, 296: 100646. PMID: 33839150, PMCID: PMC8131928, DOI: 10.1016/j.jbc.2021.100646.Peer-Reviewed Original ResearchConceptsAKT Ser/Thr kinaseInsulin receptor substrate (IRS) proteinsSer/Thr kinaseAlpha-cell functionGlobal protein translationCell functionInsulin receptor substrate-1Pancreatic alpha-cell functionDownstream target genesReceptor substrate-1Alpha cellsAlpha-cell lineGlucagon secretionSubstrate proteinsProtein translationTarget genesSubstrate-1Downstream proteinsDominant regulatorPancreatic alpha cellsMitochondrial dysfunctionCognate receptorsIRS2Normal glucose toleranceCell lines
2020
From population to neuron: exploring common mediators for metabolic problems and mental illnesses
Takayanagi Y, Ishizuka K, Laursen T, Yukitake H, Yang K, Cascella N, Ueda S, Sumitomo A, Narita Z, Horiuchi Y, Niwa M, Taguchi A, White M, Eaton W, Mortensen P, Sakurai T, Sawa A. From population to neuron: exploring common mediators for metabolic problems and mental illnesses. Molecular Psychiatry 2020, 26: 3931-3942. PMID: 33173197, PMCID: PMC8514126, DOI: 10.1038/s41380-020-00939-5.Peer-Reviewed Original ResearchConceptsMajor mental illnessOlfactory neuronal cellsInsulin resistanceMental illnessBipolar disorderNeuronal cellsPathophysiological mediatorsHigh incidenceSZ patientsCommon mediatorIrs2 knockout miceSame large cohortIRS2 tyrosine phosphorylationDanish registriesBP patientsHealthy controlsHealthy subjectsLarge cohortEpidemiological dataEpidemiological studiesKnockout miceAnimal modelsPatientsMetabolic problemsDiabetesParaventricular, subparaventricular and periventricular hypothalamic IRS4-expressing neurons are required for normal energy balance
Sutton A, Gonzalez I, Sadagurski M, Rajala M, Lu C, Allison M, Adams J, Myers M, White M, Olson D. Paraventricular, subparaventricular and periventricular hypothalamic IRS4-expressing neurons are required for normal energy balance. Scientific Reports 2020, 10: 5546. PMID: 32218485, PMCID: PMC7099088, DOI: 10.1038/s41598-020-62468-z.Peer-Reviewed Original ResearchConceptsEnergy expenditureEnergy expenditure regulationAnti-obesity therapiesFeeding-related behaviorsNormal energy balanceInsulin receptor substrate 4Negative energy balancePVH neuronsHypothalamic circuitryHypothalamic sitesEnergy balance controlFeeding suppressionParaventricular nucleusSatiety responseSubstantial obesityNormal feedingPVHNeuronsViral toolsNeural componentsHindbrain regionsObesityRequisite roleBalance controlEnergy balanceInsulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling
Riehle C, Weatherford E, Wende A, Jaishy B, Seei A, McCarty N, Rech M, Shi Q, Reddy G, Kutschke W, Oliveira K, Pires K, Anderson J, Diakos N, Weiss R, White M, Drakos S, Xiang Y, Abel E. Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling. JCI Insight 2020, 5: e134920. PMID: 32213702, PMCID: PMC7213803, DOI: 10.1172/jci.insight.134920.Peer-Reviewed Original ResearchConceptsTransverse aortic constrictionInsulin receptor substrate-1Left ventricular remodelingHeart failureVentricular remodelingCardiac hypertrophyTAC-induced LV hypertrophyPressure-overload cardiac hypertrophySevere LV dysfunctionInsulin receptor tyrosine kinase activityAkt1 activationReceptor tyrosine kinase activityLV dysfunctionLV hypertrophyWT miceInsulin resistanceLV remodelingAortic constrictionProinflammatory responseProtein kinase GInsulin receptor substrateReceptor substrate-1Kinomic profilingWT controlsTyrosine kinase activity
2019
1835-P: Deletion of Insulin Receptor Substrate 2 in AGRP Neurons Causes Beta-Cell Dysfunction
TAO R, COPPS K, WHITE M, STOEHR O. 1835-P: Deletion of Insulin Receptor Substrate 2 in AGRP Neurons Causes Beta-Cell Dysfunction. Diabetes 2019, 68 DOI: 10.2337/db19-1835-p.Peer-Reviewed Original ResearchAgRP neuronsArcuate nucleusInsulin resistanceInsulin secretionInsulin receptor substrateType 2 diabetes progressesCompensatory insulin secretionL-arginine treatmentBeta-cell compensationBeta-cell dysfunctionPeripheral insulin resistanceBeta-cell failureBeta-cell functionHigh-fat dietInsulin secretory functionType 2 diabetesSteady-state hyperglycemiaGlucose infusion rateΒ-cell dysfunctionInsulin receptor substrate 2Pancreatic β-cellsGrowth-promoting actionDiabetes progressesFat dietHyperglycemic clamp282-LB: Dysregulated FGF21 Links Hepatic Insulin Resistance to Dysfunctional BAT
STOEHR O, TAO R, COPPS K, WHITE M. 282-LB: Dysregulated FGF21 Links Hepatic Insulin Resistance to Dysfunctional BAT. Diabetes 2019, 68 DOI: 10.2337/db19-282-lb.Peer-Reviewed Original ResearchHepatic insulin resistanceFGF-21Insulin resistanceHFD feedingControl miceDiabetic phenotypeGlucose metabolismFGF-21 serum levelsWhole-body glucose metabolismGlucose uptakeInsulin-resistant liverImproved glucose toleranceWild-type miceHepatic glucose productionSevere diabetic phenotypeNormal glucose uptakeHealthy batsBAT dysfunctionSerum levelsGlucose toleranceBAT functionType miceNormal rangeInsulin actionAdenoviral infection